1(2-tertiary aminoethyl)-2-methyl-3-aryl-4-oxo-1,2,3,4-tetrahydroquinazoline derivatives and the preparation thereof



United States Patent 3,497,514 1(2-TERTIARY AMINOETHYL)-2-METHYL-3-ARYL-4-0X0-1,2,3,4-TETRAHYDROQUINAZOLINE DE- RIVATIVES AND THE PREPARATIONTHEREOF Kentaro Okumura, Kobe-shi, Toyonari Oine, Ibaragi-shi, andYoshihisa Yamada, Osaka-shi, Japan, assignors f0 Tanabe Seiyaku Co.,Ltd., Osaka, Japan, a corporation of Japan No Drawing. Filed Nov. 15,1967, Ser. No. 683,144 Claims priority, application Japan, Nov. 19,1966, 41/76,034, 41/76,036 Int. Cl. C07d 51/48 U.S. Cl. 260256.4 8Claims ABSTRACT OF THE DISCLOSURE Analgesics, anti-inflammatories,sedatives and anti-histamines in the form of new derivatives of4-oxo-1,2,3,4- tetra-hydroquinazoline and method of preparation thereof.Specifically, 1-(2-tertiary aminoethyl) 2-methyl-3-aryl-4-oxo-1,2,3,4-tetra-hydroquinazolines.

These compounds are prepared by cyclization of N- aceto-N(2-tertiaryaminoethyD-anthranflic aryl amide, followed by reduction.

The new derivatives of 4-oxo-1,2,3,4-tetra-hydroquinazoline of thepresent invention have been found to be therapeutically effective asanalgesics, anti-inflammatories, sedatives and anti-histamines. Theyconsist of the 1-(2- tertiary aminoethy1)-2-methyl 3 aryl substitutedcompounds of the formula:

wherein Ar represents a group taken from the class consisting of phenyl,tolyl or xylyl, R and R are taken from the class consisting of loweralkyl groups or, together, a pentamethylene chain.

All of the compounds prepared in the examples described hereinafter havebeen found to have sedative action. For example, the compounds areeffective to prolong sleeping time which may be induced by theadministration of barbital to the extent of about 0.5 to 4.0 times.Among them, the most effective one is 1-(2-piperidinoethyl)2-methyl-3-(2,3-xylyl)-4-oxo 1,2,3,4 tetrahydroquinazoline, which canprolong sleeping time up to 4 times at the dose of 100 mg/kg.

It has also been observed that all of the compounds prepared in theexamples show an anti-histamic effect, though the activities areslightly weaker than those of chlorpheniramine or diphenhydramine.However, some of them indicate distinguishable analgesic oranti-inflammatory effects in comparison with known compounds.

For example, 3-phenyl and 3-(2-tolyl) derivatives ofl-(2-diethylaminoethyl)-2-methyl 4 oXo-1,2,3,4-tetrahydroquinazolineshow analgesic effects approximately twice as strong as those ofaminopyrine when the compound is administered orally. The 3-(2-tolyl)derivative also has an anti-inflammatory effect which is as effective asphenyl-butazone and 1.5 times stronger than aminopyrine. Theanti-inflamrnatory actions of I-(Z-piperidinoethyl)-2-methyl-3-(2-tolyl)4 oxo 1,2,3,4 tetrahydroquinazoline and 1-(Z-dimethylaminoethyl)-2-methyl-3- phenyl 4 oxo 1,2,3,4tetrahydroquinazoline are more ICC effective than those ofphenyl-butazone when the compound is administered orally.

The process for the preparation of the compounds (I) of the presentinvention may be illustrated by the following equations:

wherein Ar, R and R have the same meanings as heretofore stated and Xrepresents the anionic moiety of inorganic acid.

The first step for intermolecular cyclization of the starting compound(II) is carried out by treating N-aceto-N- (2-tertiaryaminoethyl)-anthranilic arylamide (II) with a conventional inorganicacid such as perchloric acid, perbromic acid, hydroiodic acid,hydrobromic acid, hydrochloric acid, sulfuric acid, etc., therebyproducing the corresponding 1- (Z-tertiary aminoethyl)-2-methyl-3-aryl-4(3H)-quinazolinonium compound (III). It is preferable to use an excessof the inorganic acid. The cyclization reaction under the abovementioned conditions may be carried out satisfactorily even at roomtemperatures and the compound (III) can be easily recovered from thereaction mixture as crystals of the inorganic acid salt. The second stepfor reducing the double band in the 1,2-position of the quinazolinoniumcompound (III) can be carried out by reacting the compound (III) withsodium borohydride. The reaction is preferably carried out in a suitablesolvent such as methanol, ethanol, water, etc. at room temperature orunder cooling.

The products of the present invention are usually oily substances.However, the compounds can be readily converted into the crystallizableacid addition salts such as hydrochloride, hydrobromide, oxalate,picrate, picrolonate, etc. by conventional treatment.

As the substituents R and R alkyl groups having one to 8 carbon atomssuch as methyl, ethyl, propyl, butyl, etc. are employable in thisinvention and the alkyl homologs of the products of the Examples 1 to 6can be prepared according to the similar procedures employed in theseexamples with substantially the same results.

The starting compounds (II) of the present invention can be prepared,for instance, by acetylating N-(Z-tertiary aminoethyl)-anthranilic acidand condensing the resulting N-aceto-N-(2-tertiaryaminoethyl)-anthrani1ic acid with an arylamine.

Practical embodiments of the present invention are illustratively shownin the following examples.

EXAMPLE 1 4.9 g. of 2-[N-(Z-dimethylaminoethyl)-acetamido]- benzanilideis dissolved in 30 ml. of benzene. 4.3 ml. of 60% perchloric acid isadmixed into the solution. The resultant crystals are collected byfiltration and recrystallized from a mixture of dimethylformamide andethanol,

whereby 7.1 g. of 1-(2-dimethyl-aminoethyl)-2-methy1- 3-phenyl 4(3H)quinazolinonium perchlorate-hydroperchlorate is obtained. M.P. 255-256"C. (decomp.).

Analysis.Calculated for C H O N Cl C, 44.89%; H, 4.57%; N, 8.27%. Found:C, 45.08%; H, 4.31%; N, 8.34%.

5.0 g. of the quinazolinonium perchlorate compound thus obtained issuspended on 50 ml. of ethanol. 0.9 g. of sodium borohydride dissolvedin 50 ml. of ethanol is added dropwise to the suspension for 3 hours ati2 C. with stirring, thereby dissolving the suspended crystal gradually.After 30 minutes, the reaction mixture is evaporated to remove ethanolunder reduced pressure. A proper amount of water is added to the residueand the resultant oily substance extracted with ether. The ether layeris dried with anhydrous potassium carbonate, evaporated to remove theether and the resultant transparent viscous substance distilled underreduced pressure.

Thus, 2.0 g. of 1-(2-dimethylaminoethy1)-2-methyl-3-phenyl-4-o-xo1,2,3,4-tetrahydro-quinazoline is obtained. B.P. 250-255C./0.2 mm. Hg.

Analysis.Calculated for C H ON C, 73.75%; H, 7.49%; N, 13.58%. Found: C,73.29%; H, 7.08%; N, 13.61%.

EXAMPLE 2 4.4 g. of 2-[N-(2-dimethylaminoethyl)-acetamido]-2-Inethyl-benzanilide is dissolved in 30 ml. of ethanol. 3.5 ml. of 60%perchloric acid is admixed into the solution. The resultant crystals arecollected by filtration and recrystallized from a mixture of acetone anddirnethyl formamide, whereby 6.4 g. of 1-(Z-dimethyl-aminoethyl)-2-methyl-3 (2 tolyl)-4(3H)-quinazolinonium perchlorate-hydroperchlorateis obtained. M.P. 259-260 C. (decomp.).

Analysis.-Calculated for C H O N Cl C, 46.18%; H, 4.82%; N, 8.05%.Found: C, 46.08%; H, 4.61%; N, 7.91%.

5.0 g. of the quinazolinonium perchlorate compound thus obtained issuspended on 60 ml. of ethanol. 0.8 g. of sodium borohydride dissolvedin 90 ml. of ethanol is added dropwise to the suspension for 4.5 hoursat temperature from 5 C. to '2 C. with stirring. Then, the reactionmixture is evaporated to remove ethanol under reduced pressure and theresidue extracted with ether after adding a proper amount of water. Theether extract is dried with anhydrous potassium carbonate andevaporated. The remaining 2.5 g. of light-yellow oily substance isdissolved in ether, and an ethanol solution of picrolonic acid added tothe solution. The resultant crystals are collected by filtration andrecrystallized from ethanol, whereby 3.6 g. of1-(Z-dimethylaminoethyl)-2- methyl-3-(2-tolyl)-4-oxo-l,2,3,4-tetrahydroquinazoline perchlorate'hydroperchlorate is obtained. M.P. 260-Analysis.Calculated for C30H3306N'1: C, 61.23%; H, 5.66%; N, 16.68%.Found: C, 61.72%; H, 5.41%; N, 16.59%.

EXAMPLE 3 4.5 g. of 2-[N-(Z-dimethylaminoethyl)-acetamido]-2,3'-dimethyl-benzanilide is dissolved in 40 ml. of ether. 4 ml. of 60%perchloric acid is admixed into the solution. The resultant crystals arecollected by filtration and recrystallized from a mixture of acetone,dimethylformamide and ether. Thus, 6.1 g. of1-(2-dimethylaminoethyl)-2-methyl-3-(2,3-xylyl) 4(3H) quinazolinoniumperchlorate-hydroperch1orate is obtained. M.P. 260- 261 C. (decomp.).

Analysis-Calculated for C H O N Cl C, 47.02%; H, 5.07%; N, 7.83%. Found:C, 47.02%; H, 4.79%; N, 7.91%.

5.0 g. of the quinazolinonium perchlorate compound thus obtained issuspended on 60 ml. of ethanol. 0.75 g. of sodium borohydride dissolvedin 90 ml. of ethanol is added dropwise to the suspension for 3 hours attemperature 5 C. to 3 C. with stirring. Then, the reaction mixture isevaporated to remove ethanol under reduced pressure and the residueextracted with ether after adding a proper amount of Water. The extractis dried with anhydrous potassium carbonate and evaporated to remove theether thereby crystallizing the residue. The crystals are recrystallizedfrom n-hexane to give 2.0 g. ofI-(Z-dimethylaminoethyl)-2-methyl-3-(2,3-xylyl)-4-oxo-l,2,3,4-tetrahydroquinazoline. M.P. 102-Analysis.Calculated for C21H27ON3: C, 74.74%; H, 8.07%; N, 12.45%.Found: C, 74.49%; H, 7.89%; N, 12.42%.

EXAMPLE 4 2- [N- 2-diethylaminoethyl) -acetamido]benzanilide is reactedwith perchloric acid by similar procedure to that of Example 1, whereby1-(2-diethylaminoethyl)-2-methyl- 3 phenyl-4(3H) quinazolinoniumperchlorate-hydroperchlorate is obtained. M.P. 248-249 C. Yield: 53%(after recrystallization from dimethyl-formamide-acetoneether).

Analysis.Calculated for C H O N Cl C, 47.02%; H, 5.07%; N, 7.83%. Found:C, 46.78%; H, 4.69%; N, 8.05

The quinazolinonium perchlorate compound thus obtained (by similarprocedure to that of Example 2) is reacted with sodium borohydride andthe resultant 1-(2- dimethylaminoethyl) 2 methyl-3-phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline is converted into the oxalate. Afterrecrystallization from methanol: M.P. 182183 C. (decomp.).

Analysis.Calculated for C H O N C, 64.62%; H, 6.84%; N, 9.83%. Found: C,64.64%; H, 6.75%; N, 9.86%.

EXAMPLE 5 2- [N- (Z-diethylaminoethyl -acetamido] -2'-methylbenzanilideis reacted with perchloric acid by similar procedure to that of Example1, whereby 1-(2-diethylaminoethyl)-2-methyl-3-(2-tolyl)-4(3H)quinazolinonium perchlorate-hydroperchlorate is obtained. M.P. 193-195C. Yield: 50% (after recrystallization from ethanol).

Analysis.--Calculated for C H O N Cl -H O: C, 46.49%; H, 5.50%; N,7.39%. Found: C, 46.66%; H, 5.13%; N, 7.19%.

The quinazolinonium perchlorate compound thus obtained is made to reactwith sodium borohydride (by similar procedures to that of Example 2) andthe resultant 1-(2 diethylaminoethyl)-2-methyl-3-(2-tolyl)-4-oxo-1,2,3,4-tetrahydroquinazoline is converted into the picrate. Afterrecrystallization from methanol: M.P. 158- 160 C. (decomp.). Yield: 79%.

Analysis.-Ca1culated for C H O N C, 57.90%; H, 5.56%; N, 14.48%. Found:C, 58.04%; H, 5.38%; N, 14.18%. The oxalate: D.P. 242-245 C. (afterrecrystallization from methanol-ether; 1:2).

EXAMPLE 6 2- [N-(Z-diethylaminoethyl) acetamido]-2',3-dimethylbenzanilide is reacted with perchloric acid by similar procedure to thatof Example 1, whereby 1-(2-diethylaminoethyl)-2-methyl-3-(2,3-xylyl)4(3H) quinazolinonium perchlorate-hydroperchlorate is obtained. Afterrecrystallization from ethanol: M.P. 220222 C. Yield: 38%.

Analysis.-Calculated for C H O N Cl C, 48.94%; H, 5.55%; N, 7.45%.Found: C, 48.95%; H, 5.10%; N, 7.15%.

The quinazolinonium perchlorate compound thus obtained is reacted withsodium borohydride (by similar procedures to that of Example 3) whereby1-(2-diethylaminoethyl)-2-methyl 3(2,3-xylyl)-4-oxo-1,2,3,4-tetrahydroquinazoline is obtained. Afterrecrystallization from n-hexane: M.P. 111 C. Yield: 76%.

Analysis.Calculated for C H ON C, 75.58%; H, 8.55%; N, 11.50%. Found: C,75.66%; H, 8.53%; N, 11.48%. The oxalate: D.P. 17l-173 C. (ethanol).

In any of the foregoing examples the corresponding normal or iso propyl,butyl, amyl, hexyl, heptyl or octyl compounds may be substituted for themethyl or ethyl compounds with like effect.

EXAMPLE 7 2- [N- 2-piperidinoethyl -acetamide] -benzanilide is reactedwith perchloric acid by similar procedures to that of Example 1, whereby1-(2-piperidinoethyl)-2-methyl-3- phenyl 4(3H) quinazolinoniumperchlorate-hydroperchlorate is obtained. After recrystallization fromdimethylformamide-ethanol: M.P. 249250 C. (decomp.). Yield: 58%.

Analysis.-Calculated for C H O N Cl C, 48.17%; H, 4.98%; N, 7.66%.Found: C, 48.26%; H, 5.65%; N, 8.18%.

The quinazolinonium perchlorate compound thus obtained is reacted withsodium borohydride (by similar procedures to that of Example 2) and theresultant 1-(2- piperidinoethyl)-2-methyl 3phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline is converted into thehydrochloride. After recrystallization from ethanol: M.P. 242-244 C.(decomp.). Yield: 68%.

Analysis.-Calculated for C H ON Cl: C, 68.46%; H, 7.31%; N, 10.89%.Found: C, 68.40%; H, 7.50%; N, 10.78%.

EXAMPLE 8 2- [N- Z-piperidinoethyl) -acetamide] -2-methylbenzanilide isreacted with perchloric acid by similar procedures to that of Example 1,whereby 1-(2-piperidinoethyl)-2- methyl-3-(2-tolyl)-4( 3H)quinazolinonium perchloratehydropcrchlorate is obtained. Afterrecrystallization from dimethylformamide-ethanol: M.P. 253-255 C.(decomp.). Yield: 30%.

Analysis.-Calculated for C H O N Cl C, 49.11%; H, 5.21%; N, 7.47%.Found: C, 49.85%; H, 5.47%; N, 7.37%.

The quinazolinonium perchlorate compound thus obtained is reacted withsodium borohydride (by similar procedures to that of Example 2) and theresultant 1-(2- piperidinoethyl)-2-methyl-3-(2tolyl)-4-0xo-1,2,3,4-tetrahydroquinazoline is converted into thehydrochloride. After recrystallization from methanol: M.P. 264266 C.(decomp.).Yield: 61%.

Analysis.- Calculated for C H ON CI: C, 69.07%; H, 7.56%; N, 10.51%.Found: C, 68.67%; H, 7.58%; N, 10.57%.

EXAMPLE 9 2 [N (2 piperidinoethyl)-acetamido]-2,3'-dimethylbenzanilideis reacted with perchloric acid by similar procedure to that of Example1, whereby 1-(2-piperidinoethyl) 2 methyl3-(2,3-xylyl)-4(3H)-quinazolinonium perchlorate-hydroperchlorate isobtained. After recrystallization from dimethylformamide-ethanol: M.P.233- 235 C. (decomp.). Yield: 54%.

Analysis.-Calculated for C H O N Cl C, 50.00%; H, 5.48%; N, 7.29%.Found: C, 50.69%; H, 5.57%; N, 7.13%.

The quinazolinonium perchlorate compound thus obtained is reacted withsodium borohydride (by similar procedures to that of Example 2) and theresultant 1-(2- piperidinoethyl) 2 methyl 3-(2,3-xylyl)-4-oxo-1,2,3,4-tetrahydroquinazoline is converted into the hydrochloride. Afterrecrystallization from ethanol-ether: M.P. 250- 252 C. (decomp.). Yield:64%.

Analysis.-Calculated for C H ON CI: C, 69.63%; H, 7.79%; N, 10.15%.Found: C, 69.51%; H, 8.09%; N, 10.35%.

What we claim is:

1. 1 (2 tertiary aminoethyl) 2-methyl-3-aryl-4-oxu-1,2,3,4-tetrahydroquinazoline compound represented by the formula:

and nontoxic acid addition salts thereof, wnereln Ar represents phenyl,tolyl or xylyl group, R and R represent alkyl groups having one to 8carbon atoms or together a pentamethylene chain.

2. Compounds according to claim 1 wherein said tertiary amino isdimethyl amino, diethyl amino or piperidino.

3. Compounds according to claim 2 wherein Ar is phenyl, 2-tolyl or 2,3xylyl.

4. Compounds according to claim 2 wherein said tertiary amino ispiperidino and said Ar is 2,3-xylyl.

5. A process for preparing 1-(2-tertiary aminoethyl)-2- methyl 3aryl-4-oxo-1,2,3,4-tetrahydroquinazoline compound represented by theFormula I:

' N-Ar wherein Ar represents phenyl, tolyl or xylyl group, R and Rrepresent alkyl groups having one to 8 carbon atoms respectively ortogether a pentamethylene chain which comprises treatingN-aceto-N-(Z-tertiary aminoethyl)- anthranilic arylamide represented bythe Formula II:

wherein Ar, and R and R have the same meanings as stated above, with aninorganic acid and reacting the resultant 1- Z-tertiaryaminoethyl)-2-methyl-3-aryl-4- 3H quinazolinonium compound with an alkali metalborohydride.

6. A process according to claim 5 wherein said inorganic acid is takenfrom the class consisting of perchloric, perbromic, hydriodic,hydrobromic, hydrochloric and sulfuric.

7. A process according to claim 5 wherein said tertiary amino ispiperidino and said aryl is 2,3-xylyl.

8. A process according to claim 5 wherein said alkali metal is sodium.

References Cited UNITED STATES PATENTS 3,213,094 10/1965 Morgan et al.260-2564 3,215,697 11/1965 Hauptmann et al. 260-256.4

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner US. Cl.X.R. 424-251

